Comparison of the Efficacy of Amitriptyline and Topiramate in Prophylaxis of Cyclic Vomiting Syndrome

Objectives Cyclic vomiting syndrome (CVS) is a chronic functional gastrointestinal disorder with no certain treatment. We aimed to compare the efficacy of amitriptyline and topiramate on prophylactic therapy of CVS. Materials & Methods This randomized clinical trial (registration number: IRCT2015102316844N2) was conducted during 2016 in Isfahan, central Iran. The inclusion criteria were CVS patients (based on Rome III) aging 3-15 yr with normal physical examination, no metabolic disorder, and no gastrointestinal obstruction or renal impairment. Recruited patients were divided into two groups of amitriptyline (1 mg/kg/d) and topiramate (1-2 mg/kg/d) and were followed for 3-months. The outcome was evaluated by comparing severity of attacks (monthly frequency and duration of attacks) before and after intervention. Results Thirty-six children entered each group and two patients left the amitriptyline group. Patients and disease characteristics were similar between groups before intervention (P>0.05). The frequency of attacks (standard deviation) after intervention in amitriptyline and topiramate group was 0.91 (0.40) and 1.07 (0.55), respectively (P=0.368) and the duration of attacks (SD) after intervention were 3.43 (2.46) and 4.90 (3.03), respectively (P=0.017). Twenty-three patients (68%) in amitriptyline group and 14 patients (39%) in topiramate group stopped having attacks after intervention (P=0.016). Conclusion Amitriptyline is a better choice to reduce severity of CVS attacks compared to topiramate, in a short-term evaluation. Studies with longer follow-up are required to investigate these findings in a longer period.

Comparison of the Efficacy of Amitriptyline and Topiramate in Prophylaxis...
(up to 6 times/h), and with debilitating nausea that can cause severe dehydration and may lead to intravenous therapy (1). Other symptoms include pallor, lethargy, nausea, abdominal pain, loss of appetite, photophobia and headache (1). CVS is usually misdiagnosed with other disorders since there are no specific symptoms and diagnostic paraclinical tests for the condition (8).
The underlying mechanisms causing this disorder are not well understood, however, some theories are suggested in the literature: dysfunctional braingut interaction; corticotrophin releasing factor disorder; abnormal function of the autonomic nervous system; mitochondrial dysfunction due to DNA mutations that cause a deficiency of cellular energy production; and heightened hypothalamic stress response leading to nausea (1,2,5,8). Moreover, the relationship between CVS and migraine is suggested from a long time ago considering their similarities in clinical features and reasonable successes in treatment of CVS with anti-migraine medication (9,10).
CVS attacks may cause adverse effects including esophagitis, hematemesis, intracellular electrolyte decrease, hypertension, and syndrome of inappropriate antidiuretic hormone secretion (4).
This disorder can cause children to be absent at school, parents to be absent from work, leading to socio-economic losses, and incurring medical expenses for families (4,7). In addition, children with CVS experience 5%-15% decrease in their quality of life (6,7). These all indicate the importance of finding an effective treatment for CVS.
Various drugs have been experimented for this disorder.
In children, amitriptyline, imipramine, topiramate, propranolol, erythromycin, cyproheptadine, and combination of L-Carnitine and CoQ10 have been

What is known?
Cyclic vomiting syndrome is a chronic disease characterized by recurrent self-limited nausea and vomiting episodes with symptom-free intervals.
There is no certain treatment for cyclic vomiting syndrome yet.
Amitriptyline, imipramine, topiramate, propranolol, erythromycin, cyproheptadine, and combination of L-Carnitine and CoQ10 have been suggested to be effective in treatment of cyclic vomiting syndrome.

What is new?
Amitriptyline can be used as an effective treatment in children with cyclic vomiting syndrome with response rate of >90% in our series.
Amitriptyline has a superiority on topiramate in prophylactic treatment of cyclic vomiting syndrome.
Topiramate is not an effective drug for treatment of cyclic vomiting syndrome. suggested (2,5,6). Amitriptyline is one of the most common drugs with a favorable response (11).
Despite these findings, there is not a reliable treatment protocol for CVS yet and more clinical trials need to be performed on this issue (5).
In this study, we aimed to compare the efficacy of topiramate and amitriptyline on CVS prophylaxis. Patients who refused to fill informed consent to participate in the study and those who decided to leave the study for reasons other than adverse drug reactions were excluded. Informed consent was obtained from patients or their parents prior to the study. The study was approved by regional Besides, data on frequency and severity of their CVS attacks, history of hospitalization, and possible complications were collected retrospectively.

Materials and Methods
After enrollment of patients, they were divided into two groups randomly using block randomization and each block was allocated to one of the groups of amitriptyline or topiramate using numbered envelopes thereafter. One group was treated with 1 mg/kg/d of amitriptyline (produced by Pars Daru company in Iran) and the other group was treated with 1-2 mg/kg of topiramate (produced by Pars Daru company in Iran) twice a day. Groups were followed for 3 months after starting the medication, looking for any response to the medication. They were visited regularly during this period every two weeks. The frequency and duration of attacks and adverse drug reactions were asked in each visit as the primary outcome of the study. The mean frequency and duration of attacks in the three months of intervention were compared then to the frequency and duration of attacks before intervention. We assumed patients who stopped having attacks at least in the last month of follow-up as vomit-free patients and compared them between study groups. Moreover, patients who had ≥50% reduction in frequency or duration of attacks were compared between two groups.   We also compared the mean number of vomits per attack and the mean number of vomits per

Discussion
Amitriptyline is a tricyclic antidepressant (TCA) reported in previous studies (6,14,15) as one of the most effective treatments for CVS patients.
The efficacy of this drug has been reported 52% to 93% (6,14,16,17,18). In contrast to amitriptyline, topiramate is studied in fewer studies before and only small number of reports are available suggesting topiramate as an appropriate and effective choices for prophylactic treatment of CVS (6,12,13).
In the present study, patients showed a favorable response to both amitriptyline and topiramate regarding decrease in frequency and duration of attacks. We observed 39% full remission after topiramate administration and 68% full remission after amitriptyline administration. Andersen et al reported 73% of patients with complete remission and 18% with partial remission after a follow-up of 5 months to 10 yr (19). Moreover, in a study, 93% of their patients experienced decreased symptoms and 26% stopped having attacks after 3 months of treatment with amitriptyline (17).
In a randomized clinical trial conducted by our group, we found full remission among 65.6% of patients receiving amitriptyline after 6 months of follow-up (18). Additionally, a prospective Iranian study on children with CVS reported effectiveness of amitriptyline in 56% of their patients (20).
Our findings on efficacy of amitriptyline seem to be consistent with these reports although they had different settings, methods, and follow-up

Clinical trial registration
The study was registered in Iranian Registry of Clinical Trials (www.IRCT.ir) with registration number: IRCT2015102316844N2

Authors' Contribution
Yaghini and Saneian had the main idea of the project, designed the study, cooperated in study implementation and data collection, interpreted the data, critically reviewed the manuscript, and approved the final manuscript as submitted.
Bagherian and Badihian helped in designing, cooperated in implementation and data collection, analyzed and interpreted the data, prepared the first draft of the manuscript, and approved the final manuscript as submitted.